Genetics of obsessive-compulsive disorder and Tourette disorder

Chapter 20

Genetics of obsessive-compulsive disorder and Tourette disorder Christie L. Burtona, Csaba Bartab, Danielle Cathc,d, Daniel Gellere, Odile A. van den Heuvelf, Yin Yaog, (Obsessive Compulsive Disorder and Tourette Syndrome Working Group of the Psychiatric Genomics Consortium), Valsamma unblattj,k,l,* and Gwyneth Zaim,n,* Eapenh,i,*, Edna Gr€ a

Neurosciences & Mental Health, Hospital for Sick Children, Toronto, ON, Canada, b Institute of Medical Chemistry, Molecular Biology and

Pathobiochemistry, Semmelweis University, Budapest, Hungary, c Department of Psychiatry, Groningen University and University Medical Center Groningen, Groningen, The Netherlands, d Department of Specialist Training, Drenthe Mental Health Institution, Assen, The Netherlands, e Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States, f Amsterdam University Medical Centers, Department of Psychiatry and Department of Anatomy & Neuroscience, Vrije Universiteit Amsterdam, Amsterdam Neuroscience, Amsterdam, The Netherlands, g Lab of Statistical Genomics and Data Analysis, Intramural Program, National Institute of Mental Health, National Institutes of Health, Bethesda, MD, United States, h Department of Psychiatry, University of New South Wales, Sydney, NSW, Australia, i Academic Unit of Child Psychiatry South West Sydney, Ingham Institute and Liverpool Hospital, Sydney, NSW, Australia, j Department of Child and Adolescent Psychiatry and Psychotherapy, Psychiatric Hospital, University of Zurich, Zurich, Switzerland, k Neuroscience Center Zurich, University of Zurich and ETH Zurich, Zurich, Switzerland, l Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland, m Neurogenetics Section, Molecular Brain Science Department, Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health, Toronto, ON, Canada, n

Department of Psychiatry, University of Toronto, Toronto, ON, Canada

1 Introduction Obsessive-compulsive disorder (OCD) and Tourette disorder (TD) are chronic and debilitating neuropsychiatric disorders, affecting 1%–3% (Ruscio, Stein, Chiu, & Kessler, 2010) and 0.5%–1% (Robertson, 2015; Scharf et al., 2015) of the general population, respectively. OCD is characterized by obsessions (irrational, unwanted, and intrusive thoughts, images, or urges that generate distress) and/or compulsions (repetitive rituals to alleviate distress caused by the obsessions; American Psychiatric Association, 2013). Individuals with TD have one or more vocal or motor tics that began before age 18, and were present for more than 1 year (American Psychiatric Association, 2013; Bertelsen et al., 2014). A higher rate of comorbid OCD and TD has previously been well-documented (Hirschtritt et al., 2015; Peterson, Pine, Cohen, & Brook, 2001) and these disorders also share genetic susceptibility (Davis et al., 2013; Grados et al., 2008; Mathews & Grados, 2011; McGrath et al., 2014). This chapter discusses the genetics of OCD and TD.

1.1 Heritability and familiality of OCD and TD Family and twin studies clearly demonstrate a genetic component for both OCD and TD. First-degree relatives of individuals affected by TD are 10–100 times more likely to have TD than the general population (O’Rourke, Scharf, Yu, & Pauls, 2009). The largest clinical twin study for TD included 30 monozygotic and 13 dizygotic twins (Price, Kidd, Cohen, Pauls, & Leckman, 1985). The concordance of monozygotic twins with TD or chronic tics was 77%, but the concordance of dizygotic twins for TD or chronic tics was only 23%, suggesting a dominant genetic component in TD (O’Rourke et al., 2009). Two recent twin studies in tics and TD found heritability rates between 0.25 and 0.77, depending on phenotypic definitions (Mataix-Cols et al., 2015; Zilhao et al., 2017). Heritability estimates for OCD from twin studies are somewhat lower (.30–.65), depending on age and sex of the sample (van Grootheest, Cath, Beekman, & Boomsma, 2005; Van Grootheest, Cath, Beekman, & Boomsma, 2007). TD and OCD are also highly comorbid. Fifty percent of individuals with TD exhibit obsessive-compulsive behaviors (Albin & Mink, 2006), and conversely, about 20% of individuals * These senior authors contributed equally. Personalized Psychiatry. https://doi.org/10.1016/B978-0-12-813176-3.00020-1 Copyright © 2020 Elsevier Inc. All rights reserved.

239

240

Personalized Psychiatry

with OCD show tics (de Vries et al., 2016). Additionally, a family study reported that obsessive-compulsive symptoms (OCS) were significantly correlated in sibling pairs concordant for TD (Leckman et al., 2003). Twin studies indicate that tics and OCD may share some genetic liabilities, with genetic correlations between 0.37 and 0.58 (Guo et al., 2012; Zilhao, Smit, Boomsma, & Cath, 2016). Similarly, genome-wide association studies (GWAS) data in large clinical samples of TD and OCD indicate some shared but also distinct genetic architectures for OCD and TD, revealing a genetic correlation of 0.41, and a heritability point estimate of 0.37 and 0.58, respectively, for OCD and TD (Davis et al., 2013). A recent study from the Brainstorm consortium reported a higher genetic correlation between OCD and TD (0.7) using LD score regression (Antilla et al., 2016). Although highly correlated, each disorder had distinct correlations with other psychiatric disorders. For example, OCD was highly genetically correlated with anorexia nervosa, bipolar disorder, and schizophrenia, while TD was highly correlated with attention-deficit/hyperactivity disorder (ADHD).

1.2 Candidate gene studies in OCD and TD In the past two decades, many hypothesis-based association studies have been conducted, searching for an association between the serotonergic, glutamatergic, dopaminergic, and other systems with OCD and TD (see a selection in Table 1). The serotonergic system has been the most widely studied system in OCD because selective serotonin reuptake inhibitors (SSRIs) are the primary pharmacological OCD treatment (Bandelow et al., 2016; Davis et al., 2013; Murphy et al., 2013). Furthermore, glutamate abnormalities have been implicated in the etiology of OCD, specifically in the cortico-striato-thalamo-cortical (CSTC) circuits (Pauls, Abramovitch, Rauch, & Geller, 2014). Last, the role of the dopaminergic system in OCD has come from the effects of antipsychotics as adjunct agents to antidepressants (Pauls et al., 2014). Animal, neuroimaging, and neurochemical studies also implicate dopaminergic dysfunction in the pathophysiology of OCD (Koo, Kim, Roh, & Kim, 2010). Similarly, these systems were investigated in TD, as the glutamate receptor, ionotropic N-methyl D-aspartate (NMDA) 2B gene (GRIN2B), known to be expressed in the hippocampus, basal ganglia, and cerebral cortex, codes for subunit 2 of the NMDA receptor as well as acts as a binding site for glutamate, thus it is involved in excitatory neurotransmission (Schito et al., 1997).

1.3 Genome-wide association studies in OCD and TD With four studies to date, OCD GWAS is still in its early days. The first GWAS was conducted by the International Obsessive-Compulsive Disorder Foundation (IOCDF) Genetics Collaborative (Stewart, Yu, et al., 2013), including 1,465 OCD patients with mixed age of onset, 5,557 controls, and 400 trios. In the trio analysis, a SNP near the BTB domain containing 3 (BTBD3) reached genome-wide significance (P ¼ 3.84  108), while intronic SNPs within the DLG associated protein 1 (DLGAP1), a gene previously associated with OCD, approached genome-wide significance in the case-control analysis. No genome-wide SNPs were identified in the combined trio-case/control analysis, but the top SNPs were enriched for frontal lobe and methylation expression quantitative trait loci (eQTLs). The second GWAS was conducted by the OCD Collaborative Genetics Association Study (OCGAS) consortium on a sample of 5,061 individuals, including 1,065 families (with 1,406 childhood-onset OCD patients) and unrelated populationbased controls (Mattheisen et al., 2015). A locus near the protein tyrosine phosphatase receptor type D (PTPRD) approached significance, while markers with next-smallest P-value were near cadherin genes, CDH9 and CDH10. TABLE 1 Summary of some candidate gene studies in OCD and TD

System Serotonergic

Risk allele

Gene (SNPS/ polymorphism)

OCD

TD

SLC6A4 (5HTTLPR, rs25531)

LA allele (Brem, Grunblatt, Drechsler, Riederer, & Walitza, 2014; Taylor, 2013, 2016; Walitza et al., 2014)

LA allele (Moya et al., 2013)

HTR2A (rs6311; rs6313)

A allele (Taylor, 2016; Walitza et al., 2012)

—

MAOA

Trend, mostly in males (Brem et al., 2014; Di Nocera, Colazingari, Trabalza, Mamazza, & Bevilacqua, 2014; Liu, Yin, Wang, Zhang, & Ma,

Trend (Diaz-Anzaldua et al., 2004; Gade et al., 1998)

Genetics of obsessive-compulsive disorder and Tourette disorder Chapter 20

241

TABLE 1 Summary of some candidate gene studies in OCD and TD—cont’d

System

Gene (SNPS/ polymorphism)

Risk allele OCD

TD

2013; Mas et al., 2014; Sampaio et al., 2015; Taylor, 2013; Walitza et al., 2004)

Glutamatergic

Dopaminergic

Others

TPH1; TPH2

Trend (Brem et al., 2014; Di Nocera et al., 2014; Liu et al., 2013; Mas et al., 2014; Sampaio et al., 2015; Taylor, 2013; Walitza et al., 2004)

Trend (Comings et al., 1996; Dehning et al., 2010; Mossner, Muller-Vahl, Doring, & Stuhrmann, 2007)

HTR1B; HTR2C

Trend (Brem et al., 2014; Di Nocera et al., 2014; Liu et al., 2013; Mas et al., 2014; Sampaio et al., 2015; Taylor, 2013; Walitza et al., 2004)

Trend (Comings et al., 1996; Dehning et al., 2010; Mossner et al., 2007)

TDO2

—

Trend (Comings et al., 1996; Dehning et al., 2010; Mossner et al., 2007)

SLC1A1 (rs301443, rs12682897, rs378041)

Trend, particularly gender specific (Dickel et al., 2006; Stewart, Fagerness, et al., 2007; Stewart, Mayerfeld, et al., 2013; Taylor, 2013)

—

GRIN2B

Trend (Qin et al., 2016)

Trend (Che et al., 2015)

ADORA1; ADORA2A

—

Trend (Ciruela et al., 2006; Hettinger, Lee, Linden, & Rosin, 2001; Janik, Berdynski, Safranow, & Zekanowski, 2015)

COMT (rs4680)

Trend, particularly gender specific (Melo-Felippe et al., 2016; Taylor, 2013, 2016)

—

DRD2, ANKK1 (rs1800497)

Symmetry associated (Lochner et al., 2016), while no association with OCD (Taylor, 2013)

Risk allele (Yuan et al., 2015)

DRD4

No association with OCD (Taylor, 2013)

Trend (Asghari et al., 1995; DiazAnzaldua et al., 2004; Grice et al., 1996; Liu et al., 2014)

SLC6A3 (DAT1)

No association with OCD (Taylor, 2013)

Trend (Comings et al., 1996; DiazAnzaldua et al., 2004; Tarnok et al., 2007; Yoon et al., 2007)

BDNF

Inconsistent (Taylor, 2013; Zai et al., 2015)

—

MOG, OLIG2

Trend (Stewart, Platko, et al., 2007; Zai et al., 2004)

—

SLITRK1-5

Trend (Ozomaro et al., 2013; Song et al., 2017)

Trend (Abelson et al., 2005)

HDC

—

Trend (Ercan-Sencicek et al., 2010; Karagiannidis et al., 2013; Lei et al., 2012)

NRXN1

Trend (Noh et al., 2017)

Trend (Sundaram, Huq, Wilson, & Chugani, 2010)

BTBD9

—

Trend (Guo et al., 2012; Riviere et al., 2009)

Abbreviation: ADORA1, ADORA2A, adenosine receptor A1 or A2A; ANKK1, ankyrin repeat and kinase domain containing 1; BDNF, brain-derived neurotrophic factor; COMT, catechol-O-methyltransferase; DRD2, dopamine D2 receptor; DRD4, dopamine D4 receptor; GRIN2B, ionotropic N-methyl Daspartate (NMDA) 2B receptor; HDC, histidine decarboxylase; HTR1B, serotonin 1D-beta receptor; HTR2A, serotonin 2A receptor; HTR2C, serotonin 2C receptor; MAOA, monoamine oxidase A; MOG, myelin-oligodendrocyte glycoprotein; NRXN1, neurexin 1; OLIG2, oligodendrocyte lineage transcription factor 2; SLC1A1, glutamate transporter; SLC6A3, DAT1, dopamine transporter; SLC6A4, serotonin transporter; SLITRK1, SLIT and NTRK like family member 1; TDO2, tryptophan 2,3-dioxygenase; TPH1 & 2, tryptophan hydroxylase.

242

Personalized Psychiatry

Recently, the two previous GWAS were meta-analyzed with a total sample of 2,688 Caucasian OCD patients and 7,037 genomically matched controls (International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDFGC) and OCD Collaborative Genetics Association Studies (OCGAS), 2017). Although no markers were genome-wide significant, the SNPs with the lowest P-values tagged haplotype blocks close to, or in, cancer susceptibility 8 (CASC8/ CASC11), glutamate ionotropic receptor delta type subunit 2 (GRID2), and KIT proto-oncogene receptor tyrosine kinase (KIT). The top markers were also near or within genes identified in previous genome-wide studies: Ankyrin repeat and SOCS box containing 13 (ASB13), GRIK2, CHD20, DLGAP1, fas apoptotic inhibitory molecule 2 (FAIM2), PTPRD, and R-spondin 4 (RSPO4). Larger samples should lead to genome-wide hits, as this sample was underpowered. Finally, GWAS of OCS and traits in community, rather than clinic, samples have identified genome-wide variants. A GWAS of OCS with 6,931 participants from the Netherlands Twin Registry (NTR) study identified a genome-wide significant marker (rs8100480) in the BLOC-1 related complex subunit 8 (BORCS8 or MEF2BNB) gene and four significant genes in the myocyte enhancer factor 2B (MEF2B) family (den Braber et al., 2016). Polygenic risk based on the IOCDF GWAS significantly predicted OCS, suggesting that OCS may be a useful subclinical phenotype in gene discovery for OCD. A GWAS of obsessive-compulsive traits in a sample of Caucasian children and adolescents from the community (n ¼ 4,945) identified genome-wide significant markers in NPAS2 and PTPRD, a gene identified a previous OCD GWAS study. A hypothesis-driven GWAS demonstrated that SNPs linked to central nervous system (CNS) development, but not glutamate, were associated with obsessive-compulsive traits (Burton et al., 2015). In TD, there are no genome-wide significant loci to date from the two published GWAS studies, likely because of lack of power. The first in 2012 by the Tourette Syndrome Association International Consortium for Genetics (TSAICG) included 1,285 cases and 4,964 ancestry-matched controls (Scharf et al., 2013). The top signal was an SNP located in the collagen type XXVII alpha 1 chain (COL27A1) gene (P ¼ 1.85  106). A replication study with the top 42 SNPs of the original GWAS was performed with a sample of 609 cases and 610 controls. The top signal in the meta-analysis was at rs2060546 (P ¼ 5.8  107), in proximity of the netrin 4 (NTN4) gene on chromosome 12q22, which codes for netrin 4, an axon guidance protein expressed in the developing striatum. Many of the previous findings (26 out of 42) showed a similar trend underlining the reliability of the GWAS hits as true risk factors for TD (Paschou et al., 2014).

1.4 Copy number variation in OCD and TD To date, few copy number variation (CNV) studies have focused on OCD associations. One recent study of 307 unrelated OCD patients (including 174 cases from complete trios) and 3,681 population controls (Gazzellone et al., 2016) reported the rate of de novo CNVs in OCD was lower than other neurodevelopmental disorders (2.3%). OCD patients had CNVs in genes previously associated with OCD and TD in candidate and GWAS studies, such as PTPRD and BTBD9 (Guo et al., 2012; Mattheisen et al., 2015; Riviere et al., 2009). CNVs identified in OCD patients were also enriched in several brain relevant gene-sets, including targets of fragile X mental retardation protein, neuronal migration, and synapse formation (Gazzellone et al., 2016). A recent publication in 121 early-onset pediatric OCD patients and 124 controls, including another 820 in-house healthy controls and 1,038 Affymetrix controls screened for rare small CNVs, reported a significantly higher frequency of rare small CNVs affecting brain-related genes in the OCD patients (Grunblatt et al., 2017). Enrichment analysis of CNVs gene content confirmed the involvement of genes in synaptic and brain-related functional pathways in OCD patients that was not observed in controls. Two patients demonstrated de novo CNVs encompassing genes previously associated with neurodevelopmental disorders (NRXN1, ANKS1B, UHRF1BP1). In a pilot genome-wide study screening for CNVs in 16 adults with early-onset OCD and 12 controls, a rare small deletion encompassing FMN1 gene (Chr. 15q13.3), which was paternally inherited, was detected in a male OCD patient (Cappi et al., 2014). The FMN1 gene is known to be involved in the glutamatergic pathway, which supports the hypothesis of the involvement of this system in OCD. Another study performed a cross-disorder genome-wide CNV analysis in OCD and TD using a case-control design (2,699 cases; n ¼ 1,613 with OCD and n ¼ 1,086 with TD, n ¼ 1,789 controls) (McGrath et al., 2014). A 3.3-fold increase of large deletions was observed among OCD/TD cases compared with controls. Most deletions were located in the 16p13.11 locus, which has been linked to other neurodevelopmental disorders. Evidence was weaker in TD than in OCD cases (McGrath et al., 2014). In 188 TD cases, intronic deletions in the inner mitochondrial membrane peptidase subunit 2 (IMMP2L) gene were identified significantly more frequently than in the study and reference controls (Affymetrix) cohort (Bertelsen et al., 2014). SNP-based heritability indicates that rare variants including CNVs (minor allele frequency of < 1%) account for more variance, and thus play a bigger role, in TD than OCD (Davis et al., 2013).

Genetics of obsessive-compulsive disorder and Tourette disorder Chapter 20

243

In a case-control study of 460 individuals with TD, including 148 parent-child trios and 1,131 controls, TD cases were not enriched for de novo or transmitted rare CNVs. Pathway analysis showed enrichment of genes within histamine receptor (subtypes 1 and 2) signaling pathways, and several brain-related pathways (e.g., nervous system development, and synaptic structure and function). Several CNVs overlapped with genes previously identified in autism spectrum disorders. TD cases also had three de novo CNVs that were likely to be pathogenic, one of which disrupted multiple GABA receptor genes (Fernandez et al., 2012). A GWAS of CNVs in TD using a Latin American sample (210 cases and 285 controls) showed that large CNVs were increased among cases compared with controls (Nag et al., 2013). Of the 24 large CNVs in the cases, four duplications and two deletions were located in the collagen type VII alpha 1 chain (COL8A1) and NRXN1 gene regions—both genes have been implicated in other neurodevelopmental disorders, including autism. Two out of three NRXN1 deletions in the TD cases were de novo mutations. A recent study of rare CNVs used SNP microarray data from the TSAICG GWAS sample (Scharf et al., 2013), with a total of 2,434 TD cases and 4,093 ancestry-matched controls, reported an enrichment of global CNV burden that was prominent for large (>1 Mb), singleton events, and known, pathogenic CNVs (Huang et al., 2017). Two individual, genomewide significant loci were also identified, each conferring a substantial increase in TD risk (NRXN1 deletions, OR ¼ 20.3; contactin 6 [CNTN6] duplications, OR ¼ 10.1).

1.5 Whole exome sequencing in OCD and TD Only one study has examined 20 sporadic OCD cases and their unaffected parents using whole exome sequencing (WES), and it detected a high rate of de novo single-nucleotide variants (SNVs; Cappi et al., 2016). Additionally, nearly all de novo SNVs were in genes expressed in the human brain, and were enriched in immunological, CNS functioning and development using a Degree-Aware Disease Gene Prioritization to rank the protein-protein interaction network genes. A recent study using WES was completed in 325 TD trios from the TIC Genetics cohort and a replication sample of 186 trios from the TSA International Consortium on Genetics (n ¼ 511 total; Willsey et al., 2017). Robust evidence indicated the contribution of de novo likely gene-disrupting variants to TD. Additionally, de novo damaging variants were overrepresented in probands (RR 1.37, P ¼ 0.003) with these variants in approximately 400 genes contributing risk in 12% of clinical cases.

1.6 Pharmacogenetics of antidepressants in OCD and TD Pharmacogenetics has become increasingly important in the treatment of psychiatric disorders. Interindividual genetic variation may partly determine drug response and tolerability. (i) Pharmacokinetic Factors Pharmacokinetics (PK) refers to the body’s handling of medication, including gastrointestinal absorption, relative and absolute extracellular water volume (distribution), liver metabolism, renal clearance, protein binding, fat solubility, and active transport into the brain. PK parameters such as drug half-life (T1/2), time to maximum concentration (Tmax), as well as peak serum concentrations (Cmax) of medication are highly variable and individualized. Both PK and pharmacodynamic parameters change with age, which may lead to differences in clinical response, and adverse effect profiles in children vs adults (Geller, 1991; Murry, Crom, Reddick, Bhargava, & Evans, 1995; Vitiello & Jensen, 1995). Our understanding of genetic markers regulating oxidative hepatic pathways for drug metabolism has increased considerably in the past decade (Mrazek, 2010). Cytochromes P450 (CYP450) are a large family of proteins extensively involved in drug metabolism. Many drugs are not only substrates for these enzymes, but may also inhibit or induce enzyme activity. Polymorphisms in genes coding for CYP450 can lead to altered metabolism, with consequent influences on serum PK parameters, clinical response, and adverse events (Elliott et al., 2017). In psychiatric pharmacogenomics, genes coding for CYP450 enzymes that metabolize SSRIs are the most salient. CYP1A2, 2B6, 2C19, 2C9, 3A4, and 2D6 may all be important in drug metabolism in OCD treatment (see Table 2 for details). Only CYP2D6 and CYP2C19 have been studied in OCD using small sample sizes (Brandl et al., 2014; Muller et al., 2012; Van Nieuwerburgh, Denys, Westenberg, & Deforce, 2009). For venlafaxine, CYP2D6 nonextensive metabolism was associated with higher number of antidepressant trials (48% vs 22% with 4 trials; P ¼ 0.007), and with greater side effects (P ¼ 0.022; Brandl et al., 2014).

244

Personalized Psychiatry

TABLE 2 CYP-450 enzymes responsible for serotonergic medication metabolism. CYP 1A2

CYP 2B6

CYP 2C19

CYP 2C9

CYP 3A4

CYP 2D6

+

+

Citalopram Clomipramine

+

Desvenlafaxine

+

+

Escitalopram

+

+

Fluoxetine

+

Duloxetine

Fluvoxamine

+

+

+

+

+ +

+

+

Venlafaxine

+

+

+

+

+

+

Vilazodone Vortioxetine

+ +

Paroxetine Sertraline

+

+

Levomilnacipran Mirtazapine

+

+ +

+

+

+ +

+

+

+

Some drugs have more than one metabolic enzymatic pathway, and inhibition of one enzyme can lead to unpredictable PK parameters utilizing alternate pathways. Many medications also inhibit CYP-450 enzymes. Autoinhibition produces nonlinear pharmacokinetics, as the drug is both an inhibitor and substrate for an enzyme.

(ii) Pharmacodynamic Factors Psychotropic medications have various pharmacodynamic mechanisms of action in which neurotransmitter systems, including serotonin, glutamate, and dopamine are involved. These interacting systems have been implicated in both antiobsessive drug response and adverse effects in OCD (Zai, Brandl, Muller, Richter, & Kennedy, 2014). Serotonergic candidate genes previously examined in OCD include SLC6A4 as well as its promoter (HTTLPR), HTR2A, HTR2C, HTR1B, and TPH. Only one study (Corregiari, Bernik, Cordeiro, & Vallada, 2012) reported a significant finding between HTR2A rs6305 and nonresponders. Real, Gratacos, and Alonso (2010) and Zhang et al. (2015) both examined the glutamatergic gene SLC1A1 in relation to prospective SSRI response. They reported a significant association with rs301434 and SSRI nonresponse, and between rs301430 and fluoxetine response. Five studies investigating the dopaminergic DRD2, DRD4, COMT, and MAOA, have been conducted, but no associations were detected (Miguita, Cordeiro, Shavitt, Miguel, & Vallada, 2011; Umehara et al., 2015; Viswanath et al., 2013; Vulink et al., 2012; L. Zhang et al., 2004), except for COMT rs4680 Met/Met genotype with citalopram response (Vulink et al., 2012). Limited pharmacogenetic candidate studies examining other genes have revealed inconsistent findings (Zai et al., 2014). The first pharmacogenetic GWAS of OCD (Qin et al., 2016) in 804 OCD cases detected a significant association between antidepressant response and DISP1 rs17162912 (P ¼ 1.76 108). Further research is needed to clarify these genes’ potential roles in OCD pharmacogenetics. No study to date has investigated the pharmacogenetics of TD.

1.7 Imaging genetics of OCD and TD Imaging genetics aims to provide insight into genetic influences on brain structure and function. Only very recently, large multinational initiatives started to investigate imaging genetics with large sample sizes (e.g., ENIGMA, IMAGEN, ADNI, CHARGE) (Bearden & Thompson, 2017; Bogdan et al., 2017; Medland, Jahanshad, Neale, & Thompson, 2014; Thompson et al., 2014). No imaging genetics studies exist for TD, while few imaging genetics publications exist in OCD, mostly using candidate genes (Arnold, Macmaster, Hanna, et al., 2009; Arnold, Macmaster, Richter, et al., 2009; Atmaca et al., 2010, 2011; Gasso et al., 2015; Hesse et al., 2011; Honda et al., 2017; Mas et al., 2016; Ortiz et al., 2016; Scherk et al., 2009; Wolf et al., 2014; Wu et al., 2013). The main genetic pathways investigated in OCD are the serotonergic, glutamatergic, and

Genetics of obsessive-compulsive disorder and Tourette disorder Chapter 20

245

dopaminergic systems (Grunblatt, Hauser, & Walitza, 2014). For the serotonin system, the orbitofrontal cortex (OFC) and the raphe nuclei are associated with the 5-HTTLPR gene variant (Grunblatt et al., 2014). Further, gray matter volumes in the right frontal pole showed a trend of being reduced in 5-HTTLPR gene LA allele carriers with OCD compared with controls (Honda et al., 2017). For the glutamatergic system, the CSTC loops, the OFC, the thalamus, and the ACC were associated with several gene variations in glutamatergic genes (see Honda et al., 2017 for review). Increased concentrations of choline measured by proton magnetic resonance spectroscopy (1H MRS) in ACC of OCD patients were associated with SNPs in the glutamate receptor AMPA1 (GRIA1) (Ortiz et al., 2016). Mean diffusivity (MD) in the right anterior and posterior cerebellar lobes was associated with SLC1A1 rs3087879 in OCD patients (Gasso et al., 2015). The few studies on dopaminergic markers and imaging correlates reported a positive association between the dopamine transporter gene (SLC6A3) and the metabolism of N-acetylaspartate in the putamen (Grunblatt et al., 2014), as well as MD of the white matter in right anterior and posterior cerebellar lobes measured by MRS (Gasso et al., 2015). The complex, heterogeneous OCD phenotype is likely to be influenced by a plethora of common SNPs and multiple genetic biological pathways (Guo et al., 2012; Yu et al., 2015). Therefore, current efforts are focused on the combination of polygenic risk scores with neuroimaging, particularly in large consortia, such as the Enhancing NeuroImaging and Genetics through Meta-Analysis (ENIGMA) consortium, to overcome power issues (Bearden & Thompson, 2017). Recently, this group reported volume asymmetry between pediatric 501 OCD cases and 439 controls in the thalamus and pallidum (Kong et al., 2019). No group differences were observed in the 1,777 adults with OCD and 1,654 controls. Furthermore, pathway enrichment analysis (Mattingsdal et al., 2013), multivariate parallel independent component analysis (Meda et al., 2012), clustering analysis, weight voxel coactivation network analysis, principal component analysis (Nymberg, Jia, Ruggeri, & Schumann, 2013), machine learning (Mas et al., 2016) and other techniques (Bearden & Thompson, 2017; Bogdan et al., 2017) are being developed for diagnostic and course prediction purposes. These techniques hold great promise for the future investigation of genetic and neuronal factors underlying OCD and TD.

1.8 Epigenetics of OCD and TD The few studies conducted to date suggest some role of epigenetic alterations in the development of OCD. In a genomewide DNA methylation analysis of blood cells from 65 OCD patients and 96 healthy controls, several differentially methylated genes were identified, including previously implicated candidate genes for OCD (e.g., BCYRN1, BCOR, FGF13, HLA-DRB1, ARX, etc.) (Yue et al., 2016). These results were not replicated in a smaller study that analyzed only 14 candidate genes (Nissen et al., 2016). OCD patients also showed more DNA methylation than controls in exons of the oxytocin receptor (OXTR) using peripheral blood leukocytes in one study (Cappi et al., 2016). In a study combining methylation alterations of an amplicon at the beginning of the first intron of SLC6A4 gene concomitantly with mRNA levels in peripheral samples, pediatric OCD patients had hypermethylated levels of the amplicon compared with age-matched controls, and to adults with OCD (Grunblatt et al., 2018); however, no changes in transcription were observed. Further, in a study examining the effects of allelic variation on mRNA expression in OCD, Jaffe et al. (2014) explored genes that were differentially expressed in OCD patients using eQTLs analysis of postmortem human brain tissue involving the dorsolateral prefrontal cortex. While this study identified significant effects of genetic variation on gene expression and differentially expressed genes linked to the broad diagnosis of OCD, no clinically significant SNP-expression pairs were found. Future studies involving larger samples are indicated to elucidate the molecular mechanisms involved. The first of three association studies on DNA methylation in TD found differences in methylation in TD patients and controls in a region on chromosome 8, recently identified by genome-wide screens and mapping mutations in single families (Sanchez Delgado et al., 2014). This region includes potassium two-pore domain channel subfamily K member 9 (KCNK9) as well as trafficking protein particle complex 9 (TRAPPC9) genes. The Epigenome-Wide Association Study on tic phenotype in 1,678 controls and tic-positive individuals from the NTR (Zilhao et al., 2015) found no genome-wide significant methylation (top hits, e.g., GABBRI, BLM, and ADAM10). In the last study, TD patients demonstrated hypermethylation in the promoter and first exon of DRD2, which increased with tic severity. Few studies have assessed the role of microRNA-mediated regulation of gene expression in TD. The first identified a nucleotide variant (var321) in the SLITRK1 30 UTR, putatively leading to its stronger binding, thus with more effective repression by miR-189 (Abelson et al., 2005). However, the role of this variant in TD pathogenesis is questionable due to its very low frequency in patients (Keen-Kim & Freimer, 2006). A recent pilot study profiled the expression of 754 miRNAs in the sera of six TD patients and three unaffected controls (Rizzo et al., 2015). miR-429, involved in midbrain and hindbrain differentiation as well as synaptic transmission, was significantly underexpressed in TD patients. If this finding is replicated, measurement of circulating miR-429 could be a useful molecular biomarker to augment TD diagnosis.

246

Personalized Psychiatry

1.9 Gene × environment of OCD and TD Heritability estimates of OCD and TD indicate that specific environmental factors that increase risk and interact with genetic vulnerability are at least as important as genes to the etiology of these disorders. A population-based study of environmental risk factors for TD (Brander et al., 2017) and OCD (Brander, Perez-Vigil, Larsson, & Mataix-Cols, 2016) found that impaired fetal growth, preterm birth, breech presentation, cesarean section, and maternal smoking during pregnancy were associated with the development of both TD and OCD (Brander, Rydell, et al., 2016, 2017). The study also identified a dose-response relationship between the environmental exposures and the development of both disorders. Maternal smoking and low birth weight had previously been implicated in the development of TD (Chao, Hu, & Pringsheim, 2014). Group A streptococcal infections as a risk-modifier for TD and OCD have not been conclusively demonstrated to date (Brander, Perez-Vigil, et al., 2016; Hoekstra, Dietrich, Edwards, Elamin, & Martino, 2013). A recent systematic review acknowledged the possibility that environmental factors may only increase risk in genetically susceptible individuals (Brander, Perez-Vigil, et al., 2016).

2

Conclusion and future perspective

OCD and TD are polygenic disorders that are clinically and genetically heterogeneous, with common (in OCD) and rare (in TD) inherited or de novo risk variants, in addition to nongenetic factors, playing a substantial role in the etiology of both of these disorders (Pauls et al., 2014; Robertson et al., 2017). Elucidating the genetic underpinnings of these complex conditions has been a major challenge, and will require the combination of clinical research, genomics, gene-by-environment, and epigenomics. To date, no clinically relevant genetic markers can explain the genetic etiology of OCD and TD. Candidate gene studies have become less of a focus in psychiatric genetics, given the advancement in genomic technology and biostatistical modeling techniques to handle large dataset including GWAS, sequencing, neuroimaging, and epigenomic studies. Therefore, future directions should focus on expanding sample size and the collection of clinically meaningful data with whole genome analysis that may improve the current perspectives of these genetically complex disorders. Once we are able to identify multiple regions of interest within the whole genome analysis, fine mapping these regions with the combination of clinical, neuroimaging, epigenomics, transcriptomics, and proteomics data will ultimately refine our understanding of the functionality and role of these genetic variations in the underlying etiology of OCD and TD. To develop targeted treatments for OCD and TD, we will need to 1) dissect the genetic, epigenetic, and environmental factors on neuronal development and circuitry formation, as well as 2) understand the shared and unique pathogenesis of these two conditions.

Acknowledgments The authors would like to sincerely thank Drs. Paul D. Arnold, James A. Knowles, Carol A. Mathews, Gerald Nestadt, and Jeremiah M. Scharf for their contribution in the final editing of this chapter. We would also like to thank the Obsessive Compulsive Disorder and Tourette Syndrome Working Group of the Psychiatric Genomics Consortium for their ongoing support.

References Abelson, J. F., Kwan, K. Y., O’Roak, B. J., Baek, D. Y., Stillman, A. A., Morgan, T. M., … State, M. W. (2005). Sequence variants in SLITRK1 are associated with Tourette’s syndrome. Science, 310(5746), 317–320. https://doi.org/10.1126/science.1116502. Albin, R. L., & Mink, J. W. (2006). Recent advances in Tourette syndrome research. Trends in Neurosciences, 29(3), 175–182. https://doi.org/10.1016/j. tins.2006.01.001. American Psychiatric Association. (2013). Diagnostic and statistical manual of mental disorders (5th ed.). Washington, DC: American Psychiatric Association. Antilla, V., Bulik-Sullivan, B., Finucane, H., Bras, J., Duncan, L., & Escott-Price, V. (2016). Analysis of shared heritability in common disorders of the brain. BioRxiv. https://doi.org/10.1101/048991. Arnold, P. D., Macmaster, F. P., Hanna, G. L., Richter, M. A., Sicard, T., Burroughs, E., … Rosenberg, D. R. (2009). Glutamate system genes associated with ventral prefrontal and thalamic volume in pediatric obsessive-compulsive disorder. Brain Imaging and Behavior, 3(1), 64–76. https://doi.org/ 10.1007/s11682-008-9050-3. Arnold, P. D., Macmaster, F. P., Richter, M. A., Hanna, G. L., Sicard, T., Burroughs, E., … Rosenberg, D. R. (2009). Glutamate receptor gene (GRIN2B) associated with reduced anterior cingulate glutamatergic concentration in pediatric obsessive-compulsive disorder. Psychiatry Research, 172(2), 136–139. https://doi.org/10.1016/j.pscychresns.2009.02.005. Asghari, V., Sanyal, S., Buchwaldt, S., Paterson, A., Jovanovic, V., & Van Tol, H. H. (1995). Modulation of intracellular cyclic AMP levels by different human dopamine D4 receptor variants. Journal of Neurochemistry, 65(3), 1157–1165.

Genetics of obsessive-compulsive disorder and Tourette disorder Chapter 20

247

Atmaca, M., Onalan, E., Yildirim, H., Yuce, H., Koc, M., & Korkmaz, S. (2010). The association of myelin oligodendrocyte glycoprotein gene and white matter volume in obsessive-compulsive disorder. Journal of Affective Disorders, 124(3), 309–313. https://doi.org/10.1016/j.jad.2010.03.027. Atmaca, M., Onalan, E., Yildirim, H., Yuce, H., Koc, M., Korkmaz, S., & Mermi, O. (2011). Serotonin transporter gene polymorphism implicates reduced orbito-frontal cortex in obsessive-compulsive disorder. Journal of Anxiety Disorders, 25(5), 680–685. https://doi.org/10.1016/j.janxdis.2011.03.002. Bandelow, B., Baldwin, D., Abelli, M., Altamura, C., Dell’Osso, B., Domschke, K., … Riederer, P. (2016). Biological markers for anxiety disorders, OCD and PTSD—A consensus statement. Part I: Neuroimaging and genetics. The World Journal of Biological Psychiatry, 17(5), 321–365. https://doi.org/ 10.1080/15622975.2016.1181783. Bearden, C. E., & Thompson, P. M. (2017). Emerging global initiatives in neurogenetics: The enhancing neuroimaging genetics through meta-analysis (ENIGMA) consortium. Neuron, 94(2), 232–236. https://doi.org/10.1016/j.neuron.2017.03.033. Bertelsen, B., Melchior, L., Jensen, L. R., Groth, C., Glenthoj, B., Rizzo, R., … Tumer, Z. (2014). Intragenic deletions affecting two alternative transcripts of the IMMP2L gene in patients with Tourette syndrome. European Journal of Human Genetics, 22(11), 1283–1289. https://doi.org/10.1038/ ejhg.2014.24. Bogdan, R., Salmeron, B. J., Carey, C. E., Agrawal, A., Calhoun, V. D., Garavan, H., … Goldman, D. (2017). Imaging genetics and genomics in psychiatry: A critical review of progress and potential. Biological Psychiatry, 82(3), 165–175. https://doi.org/10.1016/j.biopsych.2016.12.030. Brander, G., Perez-Vigil, A., Larsson, H., & Mataix-Cols, D. (2016). Systematic review of environmental risk factors for obsessive-compulsive disorder: A proposed roadmap from association to causation. Neuroscience and Biobehavioral Reviews, 65, 36–62. https://doi.org/10.1016/j. neubiorev.2016.03.011. Brander, G., Rydell, M., Kuja-Halkola, R., Fernandez de la Cruz, L., Lichtenstein, P., Serlachius, E., … Mataix-Cols, D. (2016). Association of perinatal risk factors with obsessive-compulsive disorder: A population-based birth cohort, sibling control study. JAMA Psychiatry, 73(11), 1135–1144. https:// doi.org/10.1001/jamapsychiatry.2016.2095. Brander, G., Rydell, M., Kuja-Halkola, R., Fernandez de la Cruz, L., Lichtenstein, P., Serlachius, E., … Mataix-Cols, D. (2017). Perinatal risk factors in Tourette’s and chronic tic disorders: A total population sibling comparison study. Molecular Psychiatry. https://doi.org/10.1038/mp.2017.31. Brandl, E. J., Tiwari, A. K., Zhou, X., Deluce, J., Kennedy, J. L., Muller, D. J., & Richter, M. A. (2014). Influence of CYP2D6 and CYP2C19 gene variants on antidepressant response in obsessive-compulsive disorder. The Pharmacogenomics Journal, 14(2), 176–181. https://doi.org/10.1038/tpj.2013.12. Brem, S., Grunblatt, E., Drechsler, R., Riederer, P., & Walitza, S. (2014). The neurobiological link between OCD and ADHD. Attention Deficit Hyperactivity Disorders, 6(3), 175–202. https://doi.org/10.1007/s12402-014-0146-x. Burton, C. L., Crosbie, J., Erdman, L., Dupuis, A., Park, L. S., Sinopoli, V., … Arnold, P. D. (2015). A hypothesis-driven genome-wide association study of an obsessive-compulsive quantitative trait in a community-based sample of children and adolescents. In Paper presented at the World Congress of Psychiatric Genetics, Toronto. Cappi, C., Diniz, J. B., Requena, G. L., Lourenco, T., Lisboa, B. C., Batistuzzo, M. C., … Brentani, H. (2016). Epigenetic evidence for involvement of the oxytocin receptor gene in obsessive-compulsive disorder. BMC Neuroscience, 17(1), 79. https://doi.org/10.1186/s12868-016-0313-4. Cappi, C., Hounie, A. G., Mariani, D. B., Diniz, J. B., Silva, A. R., Reis, V. N., … Brentani, H. (2014). An inherited small microdeletion at 15q13.3 in a patient with early-onset obsessive-compulsive disorder. PLoS One, 9(10). https://doi.org/10.1371/journal.pone.0110198. Chao, T. K., Hu, J., & Pringsheim, T. (2014). Prenatal risk factors for Tourette syndrome: A systematic review. BMC Pregnancy and Childbirth, 14, 53. https://doi.org/10.1186/1471-2393-14-53. Che, F., Zhang, Y., Wang, G., Heng, X., Liu, S., & Du, Y. (2015). The role of GRIN2B in Tourette syndrome: Results from a transmission disequilibrium study. Journal of Affective Disorders, 187, 62–65. https://doi.org/10.1016/j.jad.2015.07.036. Ciruela, F., Casado, V., Rodrigues, R. J., Lujan, R., Burgueno, J., Canals, M., … Franco, R. (2006). Presynaptic control of striatal glutamatergic neurotransmission by adenosine A1-A2A receptor heteromers. The Journal of Neuroscience, 26(7), 2080–2087. https://doi.org/10.1523/ JNEUROSCI.3574-05.2006. Comings, D. E., Gade, R., Muhleman, D., Chiu, C., Wu, S., To, M., … MacMurray, J. P. (1996). Exon and intron variants in the human tryptophan 2,3dioxygenase gene: Potential association with Tourette syndrome, substance abuse and other disorders. Pharmacogenetics, 6(4), 307–318. Corregiari, F. M., Bernik, M., Cordeiro, Q., & Vallada, H. (2012). Endophenotypes and serotonergic polymorphisms associated with treatment response in obsessive-compulsive disorder. Clinics (Sa˜o Paulo, Brazil), 67(4), 335–340. Davis, L. K., Yu, D., Keenan, C. L., Gamazon, E. R., Konkashbaev, A. I., Derks, E. M., … Scharf, J. M. (2013). Partitioning the heritability of Tourette syndrome and obsessive compulsive disorder reveals differences in genetic architecture. PLoS Genetics, 9(10). https://doi.org/10.1371/journal. pgen.1003864. Dehning, S., Muller, N., Matz, J., Bender, A., Kerle, I., Benninghoff, J., … Zill, P. (2010). A genetic variant of HTR2C may play a role in the manifestation of Tourette syndrome. Psychiatric Genetics, 20(1), 35–38. https://doi.org/10.1097/YPG.0b013e32833511ce. den Braber, A., Zilhao, N. R., Fedko, I. O., Hottenga, J. J., Pool, R., Smit, D. J., … Boomsma, D. I. (2016). Obsessive-compulsive symptoms in a large population-based twin-family sample are predicted by clinically based polygenic scores and by genome-wide SNPs. Translational Psychiatry. 6, https://doi.org/10.1038/tp.2015.223. de Vries, F. E., Cath, D. C., Hoogendoorn, A. W., van Oppen, P., Glas, G., Veltman, D. J., … van Balkom, A. J. (2016). Tic-related versus tic-free obsessive-compulsive disorder: Clinical picture and 2-year natural course. The Journal of Clinical Psychiatry, 77(10), e1240–e1247. https://doi. org/10.4088/JCP.14m09736. Diaz-Anzaldua, A., Joober, R., Riviere, J. B., Dion, Y., Lesperance, P., Richer, F., … Montreal Tourette Syndrome Study Group (2004). Tourette syndrome and dopaminergic genes: A family-based association study in the French Canadian founder population. Molecular Psychiatry, 9(3), 272–277. https://doi.org/10.1038/sj.mp.4001411.

248

Personalized Psychiatry

Dickel, D. E., Veenstra-VanderWeele, J., Cox, N. J., Wu, X., Fischer, D. J., Van Etten-Lee, M., … Hanna, G. L. (2006). Association testing of the positional and functional candidate gene SLC1A1/EAAC1 in early-onset obsessive-compulsive disorder. Archives of General Psychiatry, 63(7), 778–785. https://doi.org/10.1001/archpsyc.63.7.778. Di Nocera, F., Colazingari, S., Trabalza, A., Mamazza, L., & Bevilacqua, A. (2014). Association of TPH2 and dopamine receptor gene polymorphisms with obsessive-compulsive symptoms and perfectionism in healthy subjects. Psychiatry Research, 220(3), 1172–1173. https://doi.org/10.1016/j. psychres.2014.09.015. Elliott, L. S., Henderson, J. C., Neradilek, M. B., Moyer, N. A., Ashcraft, K. C., & Thirumaran, R. K. (2017). Clinical impact of pharmacogenetic profiling with a clinical decision support tool in polypharmacy home health patients: A prospective pilot randomized controlled trial. PLoS One, 12(2). https:// doi.org/10.1371/journal.pone.0170905. Ercan-Sencicek, A. G., Stillman, A. A., Ghosh, A. K., Bilguvar, K., O’Roak, B. J., Mason, C. E., … State, M. W. (2010). L-histidine decarboxylase and Tourette’s syndrome. The New England Journal of Medicine, 362(20), 1901–1908. https://doi.org/10.1056/NEJMoa0907006. Fernandez, T. V., Sanders, S. J., Yurkiewicz, I. R., Ercan-Sencicek, A. G., Kim, Y. S., Fishman, D. O., … State, M. W. (2012). Rare copy number variants in Tourette syndrome disrupt genes in histaminergic pathways and overlap with autism. Biological Psychiatry, 71(5), 392–402. https://doi.org/ 10.1016/j.biopsych.2011.09.034. Gade, R., Muhleman, D., Blake, H., MacMurray, J., Johnson, P., Verde, R., … Comings, D. E. (1998). Correlation of length of VNTR alleles at the Xlinked MAOA gene and phenotypic effect in Tourette syndrome and drug abuse. Molecular Psychiatry, 3(1), 50–60. Gasso, P., Ortiz, A. E., Mas, S., Morer, A., Calvo, A., Bargallo, N., … Lazaro, L. (2015). Association between genetic variants related to glutamatergic, dopaminergic and neurodevelopment pathways and white matter microstructure in child and adolescent patients with obsessive-compulsive disorder. Journal of Affective Disorders, 186, 284–292. https://doi.org/10.1016/j.jad.2015.07.035. Gazzellone, M. J., Zarrei, M., Burton, C. L., Walker, S., Uddin, M., Shaheen, S. M., … Scherer, S. W. (2016). Uncovering obsessive-compulsive disorder risk genes in a pediatric cohort by high-resolution analysis of copy number variation. Journal of Neurodevelopmental Disorders, 8, 36. https://doi.org/ 10.1186/s11689-016-9170-9. Geller, B. (1991). Psychopharmacology of children and adolescents: Pharmacokinetics and relationships of plasma/serum levels to response. Psychopharmacology Bulletin, 27(4), 401–409. Grados, M. A., Mathews, C. A., & Tourette Syndrome Association International Consortium for Genetics. (2008). Latent class analysis of Gilles de la Tourette syndrome using comorbidities: Clinical and genetic implications. Biological Psychiatry, 64(3), 219–225. https://doi.org/10.1016/j. biopsych.2008.01.019. Grice, D. E., Leckman, J. F., Pauls, D. L., Kurlan, R., Kidd, K. K., Pakstis, A. J., … Gelernter, J. (1996). Linkage disequilibrium between an allele at the dopamine D4 receptor locus and Tourette syndrome, by the transmission-disequilibrium test. American Journal of Human Genetics, 59(3), 644–652. Grunblatt, E., Hauser, T. U., & Walitza, S. (2014). Imaging genetics in obsessive-compulsive disorder: Linking genetic variations to alterations in neuroimaging. Progress in Neurobiology, 121, 114–124. https://doi.org/10.1016/j.pneurobio.2014.07.003. Grunblatt, E., Marinova, Z., Roth, A., Gardini, E., Ball, J., Geissler, J., … Walitza, S. (2018). Combining genetic and epigenetic parameters of the serotonin transporter gene in obsessive-compulsive disorder. Journal of Psychiatric Research, 96, 209–217. https://doi.org/10.1016/j.jpsychires.2017.10.010. Grunblatt, E., Oneda, B., Ekici, A. B., Ball, J., Geissler, J., Uebe, S., … Walitza, S. (2017). High resolution chromosomal microarray analysis in paediatric obsessive-compulsive disorder. BMC Medical Genomics, 10(1), 68. https://doi.org/10.1186/s12920-017-0299-5. Guo, Y., Su, L., Zhang, J., Lei, J., Deng, X., Xu, H., … Deng, H. (2012). Analysis of the BTBD9 and HTR2C variants in Chinese Han patients with Tourette syndrome. Psychiatric Genetics, 22(6), 300–303. https://doi.org/10.1097/YPG.0b013e32835862b1. Hesse, S., Stengler, K., Regenthal, R., Patt, M., Becker, G. A., Franke, A., … Sabri, O. (2011). The serotonin transporter availability in untreated earlyonset and late-onset patients with obsessive-compulsive disorder. The International Journal of Neuropsychopharmacology, 14(5), 606–617. https:// doi.org/10.1017/S1461145710001604. Hettinger, B. D., Lee, A., Linden, J., & Rosin, D. L. (2001). Ultrastructural localization of adenosine A2A receptors suggests multiple cellular sites for modulation of GABAergic neurons in rat striatum. The Journal of Comparative Neurology, 431(3), 331–346. Hirschtritt, M. E., Lee, P. C., Pauls, D. L., Dion, Y., Grados, M. A., Illmann, C., … Tourette Syndrome Association International Consortium for Genetics. (2015). Lifetime prevalence, age of risk, and genetic relationships of comorbid psychiatric disorders in Tourette syndrome. JAMA Psychiatry, 72(4), 325–333. https://doi.org/10.1001/jamapsychiatry.2014.2650. Hoekstra, P. J., Dietrich, A., Edwards, M. J., Elamin, I., & Martino, D. (2013). Environmental factors in Tourette syndrome. Neuroscience and Biobehavioral Reviews, 37(6), 1040–1049. https://doi.org/10.1016/j.neubiorev.2012.10.010. Honda, S., Nakao, T., Mitsuyasu, H., Okada, K., Gotoh, L., Tomita, M., … Kanba, S. (2017). A pilot study exploring the association of morphological changes with 5-HTTLPR polymorphism in OCD patients. Annals of General Psychiatry, 16, 2. https://doi.org/10.1186/s12991-017-0126-6. Huang, A. Y., Yu, D., Davis, L. K., Sul, J. H., Tsetsos, F., Ramensky, V., … Gilles de la Tourette Syndrome GWAS Replication Initiative (GGRI). (2017). Rare copy number variants in NRXN1 and CNTN6 increase risk for Tourette syndrome. Neuron, 94(6), 1101–1111. e1107. https://doi.org/10.1016/ j.neuron.2017.06.010. International Obsessive Compulsive Disorder Foundation Genetics Collaborative (IOCDF-GC) and OCD Collaborative Genetics Association Studies (OCGAS). (2017). Revealing the complex genetic architecture of obsessive-compulsive disorder using meta-analysis. Molecular Psychiatry, https://doi.org/10.1038/mp.2017.154. Jaffe, A. E., Deep-Soboslay, A., Tao, R., Hauptman, D. T., Kaye, W. H., Arango, V., … Kleinman, J. E. (2014). Genetic neuropathology of obsessive psychiatric syndromes. Translational Psychiatry, 4, e432. https://doi.org/10.1038/tp.2014.68.

Genetics of obsessive-compulsive disorder and Tourette disorder Chapter 20

249

Janik, P., Berdynski, M., Safranow, K., & Zekanowski, C. (2015). Association of ADORA1 rs2228079 and ADORA2A rs5751876 polymorphisms with Gilles de la Tourette syndrome in the Polish population. PLoS One, 10(8). https://doi.org/10.1371/journal.pone.0136754. Karagiannidis, I., Dehning, S., Sandor, P., Tarnok, Z., Rizzo, R., Wolanczyk, T., … Paschou, P. (2013). Support of the histaminergic hypothesis in Tourette syndrome: Association of the histamine decarboxylase gene in a large sample of families. Journal of Medical Genetics, 50(11), 760–764. https://doi. org/10.1136/jmedgenet-2013-101637. Keen-Kim, D., & Freimer, N. B. (2006). Genetics and epidemiology of Tourette syndrome. Journal of Child Neurology, 21(8), 665–671. https://doi.org/ 10.1177/08830738060210081101. Kong, X. Z., Boedhoe, P. S. W., Abe, Y., Alonso, P., Ameis, S. H., Arnold, P. D., … Francks, C. (2019). Mapping cortical and subcortical asymmetry in obsessive-compulsive disorder: Findings from the ENIGMA consortium. Biological Psychiatry, https://doi.org/10.1016/j.biopsych.2019.04.022 [Epub ahead of print]. Koo, M. S., Kim, E. J., Roh, D., & Kim, C. H. (2010). Role of dopamine in the pathophysiology and treatment of obsessive-compulsive disorder. Expert Review of Neurotherapeutics, 10(2), 275–290. https://doi.org/10.1586/ern.09.148. Leckman, J. F., Pauls, D. L., Zhang, H., Rosario-Campos, M. C., Katsovich, L., Kidd, K. K., … Tourette Syndrome Association International Consortium for Genetics. (2003). Obsessive-compulsive symptom dimensions in affected sibling pairs diagnosed with Gilles de la Tourette syndrome. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 116B(1), 60–68. https://doi.org/10.1002/ajmg.b.10001. Lei, J., Deng, X., Zhang, J., Su, L., Xu, H., Liang, H., … Deng, H. (2012). Mutation screening of the HDC gene in Chinese Han patients with Tourette syndrome. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 159B(1), 72–76. https://doi.org/10.1002/ajmg.b.32003. Liu, S., Cui, J., Zhang, X., Wu, W., Niu, H., Ma, X., … Yi, M. (2014). Variable number tandem repeats in dopamine receptor D4 in Tourette’s syndrome. Movement Disorders, 29(13), 1687–1691. https://doi.org/10.1002/mds.26027. Liu, S., Yin, Y., Wang, Z., Zhang, X., & Ma, X. (2013). Association study between MAO-A gene promoter VNTR polymorphisms and obsessivecompulsive disorder. Journal of Anxiety Disorders, 27(4), 435–437. https://doi.org/10.1016/j.janxdis.2013.04.005. Lochner, C., McGregor, N., Hemmings, S., Harvey, B. H., Breet, E., Swanevelder, S., & Stein, D. J. (2016). Symmetry symptoms in obsessive-compulsive disorder: Clinical and genetic correlates. Revista Brasileira de Psiquiatria, 38(1), 17–23. https://doi.org/10.1590/1516-4446-2014-1619. Mas, S., Gasso, P., Morer, A., Calvo, A., Bargallo, N., Lafuente, A., & Lazaro, L. (2016). Integrating genetic, neuropsychological and neuroimaging data to model early-onset obsessive compulsive disorder severity. PLoS One, 11(4). https://doi.org/10.1371/journal.pone.0153846. Mas, S., Pagerols, M., Gasso, P., Ortiz, A., Rodriguez, N., Morer, A., … Lazaro, L. (2014). Role of GAD2 and HTR1B genes in early-onset obsessivecompulsive disorder: Results from transmission disequilibrium study. Genes, Brain, and Behavior, 13(4), 409–417. https://doi.org/10.1111/ gbb.12128. Mataix-Cols, D., Isomura, K., Perez-Vigil, A., Chang, Z., Ruck, C., Larsson, K. J., … Lichtenstein, P. (2015). Familial risks of Tourette syndrome and chronic tic disorders. A population-based cohort study. JAMA Psychiatry, 72(8), 787–793. https://doi.org/10.1001/jamapsychiatry.2015.0627. Mathews, C. A., & Grados, M. A. (2011). Familiality of Tourette syndrome, obsessive-compulsive disorder, and attention-deficit/hyperactivity disorder: Heritability analysis in a large sib-pair sample. Journal of the American Academy of Child and Adolescent Psychiatry, 50(1), 46–54. https://doi.org/ 10.1016/j.jaac.2010.10.004. Mattheisen, M., Samuels, J. F., Wang, Y., Greenberg, B. D., Fyer, A. J., McCracken, J. T., … Nestadt, G. (2015). Genome-wide association study in obsessive-compulsive disorder: Results from the OCGAS. Molecular Psychiatry, 20(3), 337–344. https://doi.org/10.1038/mp.2014.43. Mattingsdal, M., Brown, A. A., Djurovic, S., Sonderby, I. E., Server, A., Melle, I., … Andreassen, O. A. (2013). Pathway analysis of genetic markers associated with a functional MRI faces paradigm implicates polymorphisms in calcium responsive pathways. NeuroImage, 70, 143–149. https:// doi.org/10.1016/j.neuroimage.2012.12.035. McGrath, L. M., Yu, D., Marshall, C., Davis, L. K., Thiruvahindrapuram, B., Li, B., … Scharf, J. M. (2014). Copy number variation in obsessivecompulsive disorder and Tourette syndrome: A cross-disorder study. Journal of the American Academy of Child and Adolescent Psychiatry, 53 (8), 910–919. https://doi.org/10.1016/j.jaac.2014.04.022. Meda, S. A., Narayanan, B., Liu, J., Perrone-Bizzozero, N. I., Stevens, M. C., Calhoun, V. D., … Pearlson, G. D. (2012). A large scale multivariate parallel ICA method reveals novel imaging-genetic relationships for Alzheimer’s disease in the ADNI cohort. NeuroImage, 60(3), 1608–1621. https://doi.org/ 10.1016/j.neuroimage.2011.12.076. Medland, S. E., Jahanshad, N., Neale, B. M., & Thompson, P. M. (2014). Whole-genome analyses of whole-brain data: Working within an expanded search space. Nature Neuroscience, 17(6), 791–800. https://doi.org/10.1038/nn.3718. Melo-Felippe, F. B., de Salles Andrade, J. B., Giori, I. G., Vieira-Fonseca, T., Fontenelle, L. F., & Kohlrausch, F. B. (2016). Catechol-O-methyltransferase gene polymorphisms in specific obsessive-compulsive disorder patients’ subgroups. Journal of Molecular Neuroscience, 58(1), 129–136. https://doi. org/10.1007/s12031-015-0697-0. Miguita, K., Cordeiro, Q., Shavitt, R. G., Miguel, E. C., & Vallada, H. (2011). Association study between genetic monoaminergic polymorphisms and OCD response to clomipramine treatment. Arquivos de Neuro-Psiquiatria, 69(2B), 283–287. Mossner, R., Muller-Vahl, K. R., Doring, N., & Stuhrmann, M. (2007). Role of the novel tryptophan hydroxylase-2 gene in Tourette syndrome. Molecular Psychiatry, 12(7), 617–619. https://doi.org/10.1038/sj.mp.4002004. Moya, P. R., Wendland, J. R., Rubenstein, L. M., Timpano, K. R., Heiman, G. A., Tischfield, J. A., … Murphy, D. L. (2013). Common and rare alleles of the serotonin transporter gene, SLC6A4, associated with Tourette’s disorder. Movement Disorders, 28(9), 1263–1270. https://doi.org/10.1002/ mds.25460. Mrazek, D. A. (2010). Psychiatric pharmacogenomic testing in clinical practice. Dialogues in Clinical Neuroscience, 12(1), 69–76.

250

Personalized Psychiatry

Muller, D. J., Brandl, E. J., Hwang, R., Tiwari, A. K., Sturgess, J. E., Zai, C. C., … Richter, M. A. (2012). The AmpliChip(R) CYP450 test and response to treatment in schizophrenia and obsessive compulsive disorder: A pilot study and focus on cases with abnormal CYP2D6 drug metabolism. Genetic Testing and Molecular Biomarkers, 16(8), 897–903. https://doi.org/10.1089/gtmb.2011.0327. Murphy, D. L., Moya, P. R., Fox, M. A., Rubenstein, L. M., Wendland, J. R., & Timpano, K. R. (2013). Anxiety and affective disorder comorbidity related to serotonin and other neurotransmitter systems: Obsessive-compulsive disorder as an example of overlapping clinical and genetic heterogeneity. Philosophical Transactions of the Royal Society of London Series B, Biological Sciences, 368(1615), 20120435. https://doi.org/10.1098/ rstb.2012.0435. Murry, D. J., Crom, W. R., Reddick, W. E., Bhargava, R., & Evans, W. E. (1995). Liver volume as a determinant of drug clearance in children and adolescents. Drug Metabolism and Disposition, 23(10), 1110–1116. Nag, A., Bochukova, E. G., Kremeyer, B., Campbell, D. D., Muller, H., Valencia-Duarte, A. V., … Ruiz-Linares, A. (2013). CNV analysis in Tourette syndrome implicates large genomic rearrangements in COL8A1 and NRXN1. PLoS One, 8(3). https://doi.org/10.1371/journal.pone.0059061. Nissen, J. B., Hansen, C. S., Starnawska, A., Mattheisen, M., Borglum, A. D., Buttenschon, H. N., & Hollegaard, M. (2016). DNA methylation at the neonatal state and at the time of diagnosis: Preliminary support for an association with the estrogen receptor 1, gamma-aminobutyric acid B receptor 1, and myelin oligodendrocyte glycoprotein in female adolescent patients with OCD. Frontiers in Psychiatry, 7, 35. https://doi.org/10.3389/ fpsyt.2016.00035. Noh, H. J., Tang, R., Flannick, J., O’Dushlaine, C., Swofford, R., Howrigan, D., … Lindblad-Toh, K. (2017). Integrating evolutionary and regulatory information with a multispecies approach implicates genes and pathways in obsessive-compulsive disorder. Nature Communications, 8(1), 774. https://doi.org/10.1038/s41467-017-00831-x. Nymberg, C., Jia, T., Ruggeri, B., & Schumann, G. (2013). Analytical strategies for large imaging genetic datasets: Experiences from the IMAGEN study. Annals of the New York Academy of Sciences, 1282, 92–106. https://doi.org/10.1111/nyas.12088. O’Rourke, J. A., Scharf, J. M., Yu, D., & Pauls, D. L. (2009). The genetics of Tourette syndrome: A review. Journal of Psychosomatic Research, 67(6), 533–545. https://doi.org/10.1016/j.jpsychores.2009.06.006. Ortiz, A. E., Gasso, P., Mas, S., Falcon, C., Bargallo, N., Lafuente, A., & Lazaro, L. (2016). Association between genetic variants of serotonergic and glutamatergic pathways and the concentration of neurometabolites of the anterior cingulate cortex in paediatric patients with obsessive-compulsive disorder. The World Journal of Biological Psychiatry, 17(5), 394–404. https://doi.org/10.3109/15622975.2015.1111524. Ozomaro, U., Cai, G., Kajiwara, Y., Yoon, S., Makarov, V., Delorme, R., … Grice, D. E. (2013). Characterization of SLITRK1 variation in obsessivecompulsive disorder. PLoS One, 8(8), e70376. https://doi.org/10.1371/journal.pone.0070376. Paschou, P., Yu, D., Gerber, G., Evans, P., Tsetsos, F., Davis, L. K., … Scharf, J. M. (2014). Genetic association signal near NTN4 in Tourette syndrome. Annals of Neurology, 76(2), 310–315. https://doi.org/10.1002/ana.24215. Pauls, D. L., Abramovitch, A., Rauch, S. L., & Geller, D. A. (2014). Obsessive-compulsive disorder: An integrative genetic and neurobiological perspective. Nature Reviews Neuroscience, 15(6), 410–424. https://doi.org/10.1038/nrn3746. Peterson, B. S., Pine, D. S., Cohen, P., & Brook, J. S. (2001). Prospective, longitudinal study of tic, obsessive-compulsive, and attention-deficit/ hyperactivity disorders in an epidemiological sample. Journal of the American Academy of Child and Adolescent Psychiatry, 40(6), 685–695. https://doi.org/10.1097/00004583-200106000-00014. Price, R. A., Kidd, K. K., Cohen, D. J., Pauls, D. L., & Leckman, J. F. (1985). A twin study of Tourette syndrome. Archives of General Psychiatry, 42(8), 815–820. Qin, H., Samuels, J. F., Wang, Y., Zhu, Y., Grados, M. A., Riddle, M. A., … Shugart, Y. Y. (2016). Whole-genome association analysis of treatment response in obsessive-compulsive disorder. Molecular Psychiatry, 21(2), 270–276. https://doi.org/10.1038/mp.2015.32. Real, E., Gratacos, M., Alonso, P., et al. (2010). Pharmacological resistance level in OCD patients without a stressful life event at onset of the disorder is associated with a polymorphism of the glutamate transporter gene (SLC1A1). In Paper presented at the 18th world congress of psychiatric genetics. Athens, Greece. Riviere, J. B., Xiong, L., Levchenko, A., St-Onge, J., Gaspar, C., Dion, Y., … Montreal Tourette Study Group. (2009). Association of intronic variants of the BTBD9 gene with Tourette syndrome. Archives of Neurology, 66(10), 1267–1272. https://doi.org/10.1001/archneurol.2009.213. Rizzo, R., Ragusa, M., Barbagallo, C., Sammito, M., Gulisano, M., Cali, P. V., … Purrello, M. (2015). Circulating miRNAs profiles in Tourette syndrome: Molecular data and clinical implications. Molecular Brain, 8, 44. https://doi.org/10.1186/s13041-015-0133-y. Robertson, M. M. (2015). Corrections. A personal 35 year perspective on Gilles de la Tourette syndrome: Assessment, investigations, and management. Lancet Psychiatry, 2(4), 291. https://doi.org/10.1016/S2215-0366(15)00131-5. Robertson, M. M., Eapen, V., Singer, H. S., Martino, D., Scharf, J. M., Paschou, P., … Leckman, J. F. (2017). Gilles de la Tourette syndrome. ReviewNature Reviews. Disease Primers, 3, 16097. https://doi.org/10.1038/nrdp.2016.97. Ruscio, A. M., Stein, D. J., Chiu, W. T., & Kessler, R. C. (2010). The epidemiology of obsessive-compulsive disorder in the National Comorbidity Survey Replication. Molecular Psychiatry, 15(1), 53–63. https://doi.org/10.1038/mp.2008.94. Sampaio, A. S., Hounie, A. G., Petribu, K., Cappi, C., Morais, I., Vallada, H., … Miguel, E. C. (2015). COMT and MAO-A polymorphisms and obsessivecompulsive disorder: A family-based association study. PLoS One, 10(3). https://doi.org/10.1371/journal.pone.0119592. Sanchez Delgado, M., Camprubi, C., Tumer, Z., Martinez, F., Mila, M., & Monk, D. (2014). Screening individuals with intellectual disability, autism and Tourette’s syndrome for KCNK9 mutations and aberrant DNA methylation within the 8q24 imprinted cluster. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 165B(6), 472–478. https://doi.org/10.1002/ajmg.b.32250. Scharf, J. M., Miller, L. L., Gauvin, C. A., Alabiso, J., Mathews, C. A., & Ben-Shlomo, Y. (2015). Population prevalence of Tourette syndrome: A systematic review and meta-analysis. Movement Disorders, 30(2), 221–228. https://doi.org/10.1002/mds.26089.

Genetics of obsessive-compulsive disorder and Tourette disorder Chapter 20

251

Scharf, J. M., Yu, D., Mathews, C. A., Neale, B. M., Stewart, S. E., Fagerness, J. A., … Pauls, D. L. (2013). Genome-wide association study of Tourette’s syndrome. Molecular Psychiatry, 18(6), 721–728. https://doi.org/10.1038/mp.2012.69. Scherk, H., Backens, M., Schneider-Axmann, T., Kraft, S., Kemmer, C., Usher, J., … Gruber, O. (2009). Dopamine transporter genotype influences Nacetyl-aspartate in the left putamen. The World Journal of Biological Psychiatry, 10(4 Pt. 2), 524–530. https://doi.org/10.1080/15622970701586349. Schito, A. M., Pizzuti, A., Di Maria, E., Schenone, A., Ratti, A., Defferrari, R., … Mandich, P. (1997). mRNA distribution in adult human brain of GRIN2B, a N-methyl-D-aspartate (NMDA) receptor subunit. Neuroscience Letters, 239(1), 49–53. Song, M., Mathews, C. A., Stewart, S. E., Shmelkov, S. V., Mezey, J. G., Rodriguez-Flores, J. L., … Glatt, C. E. (2017). Rare synaptogenesis-impairing mutations in SLITRK5 are associated with obsessive compulsive disorder. PLoS One, 12(1). https://doi.org/10.1371/journal.pone.0169994. Stewart, S. E., Fagerness, J. A., Platko, J., Smoller, J. W., Scharf, J. M., Illmann, C., … Pauls, D. L. (2007). Association of the SLC1A1 glutamate transporter gene and obsessive-compulsive disorder. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 144B(8), 1027–1033. https://doi.org/10.1002/ajmg.b.30533. Stewart, S. E., Mayerfeld, C., Arnold, P. D., Crane, J. R., O’Dushlaine, C., Fagerness, J. A., … Mathews, C. A. (2013). Meta-analysis of association between obsessive-compulsive disorder and the 3’ region of neuronal glutamate transporter gene SLC1A1. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 162B(4), 367–379. https://doi.org/10.1002/ajmg.b.32137. Stewart, S. E., Platko, J., Fagerness, J., Birns, J., Jenike, E., Smoller, J. W., … Pauls, D. L. (2007). A genetic family-based association study of OLIG2 in obsessive-compulsive disorder. Archives of General Psychiatry, 64(2), 209–214. https://doi.org/10.1001/archpsyc.64.2.209. Stewart, S. E., Yu, D., Scharf, J. M., Neale, B. M., Fagerness, J. A., Mathews, C. A., … Pauls, D. L. (2013). Genome-wide association study of obsessivecompulsive disorder. Molecular Psychiatry, 18(7), 788–798. https://doi.org/10.1038/mp.2012.85. Sundaram, S. K., Huq, A. M., Wilson, B. J., & Chugani, H. T. (2010). Tourette syndrome is associated with recurrent exonic copy number variants. Neurology, 74(20), 1583–1590. https://doi.org/10.1212/WNL.0b013e3181e0f147. Tarnok, Z., Ronai, Z., Gervai, J., Kereszturi, E., Gadoros, J., Sasvari-Szekely, M., & Nemoda, Z. (2007). Dopaminergic candidate genes in Tourette syndrome: Association between tic severity and 3’ UTR polymorphism of the dopamine transporter gene. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 144B(7), 900–905. https://doi.org/10.1002/ajmg.b.30517. Taylor, S. (2013). Molecular genetics of obsessive-compulsive disorder: A comprehensive meta-analysis of genetic association studies. Molecular Psychiatry, 18(7), 799–805. https://doi.org/10.1038/mp.2012.76. Taylor, S. (2016). Disorder-specific genetic factors in obsessive-compulsive disorder: A comprehensive meta-analysis. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 171B(3), 325–332. https://doi.org/10.1002/ajmg.b.32407. Thompson, P. M., Stein, J. L., Medland, S. E., Hibar, D. P., Vasquez, A. A., Renteria, M. E., … Alzheimer’s Disease Neuroimaging Initiative (2014). The ENIGMA Consortium: Large-scale collaborative analyses of neuroimaging and genetic data. Brain Imaging and Behavior, 8(2), 153–182. https://doi. org/10.1007/s11682-013-9269-5. Umehara, H., Numata, S., Tajima, A., Kinoshita, M., Nakaaki, S., Imoto, I., … Ohmori, T. (2015). No association between the COMT Val158Met polymorphism and the long-term clinical response in obsessive-compulsive disorder in the Japanese population. Human Psychopharmacology, 30(5), 372–376. https://doi.org/10.1002/hup.2485. van Grootheest, D. S., Cath, D. C., Beekman, A. T., & Boomsma, D. I. (2005). Twin studies on obsessive-compulsive disorder: A review. Twin Research and Human Genetics, 8(5), 450–458. https://doi.org/10.1375/183242705774310060. Van Grootheest, D. S., Cath, D. C., Beekman, A. T., & Boomsma, D. I. (2007). Genetic and environmental influences on obsessive-compulsive symptoms in adults: A population-based twin-family study. Psychological Medicine, 37(11), 1635–1644. https://doi.org/10.1017/S0033291707000980. Van Nieuwerburgh, F. C., Denys, D. A., Westenberg, H. G., & Deforce, D. L. (2009). Response to serotonin reuptake inhibitors in OCD is not influenced by common CYP2D6 polymorphisms. International Journal of Psychiatry in Clinical Practice, 13(1), 345–348. https://doi.org/10.3109/ 13651500902903016. Viswanath, B., Taj, M. J. R., Purushottam, M., Kandavel, T., Shetty, P. H., Reddy, Y. C., & Jain, S. (2013). No association between DRD4 gene and SRI treatment response in obsessive compulsive disorder: Need for a novel approach. Asian Journal of Psychiatry, 6(4), 347–348. https://doi.org/10.1016/ j.ajp.2013.03.003. Vitiello, B., & Jensen, P. S. (1995). Developmental perspectives in pediatric psychopharmacology. Psychopharmacology Bulletin, 31(1), 75–81. Vulink, N. C., Westenberg, H. G., van Nieuwerburgh, F., Deforce, D., Fluitman, S. B., Meinardi, J. S., & Denys, D. (2012). Catechol-O-methyltransferase gene expression is associated with response to citalopram in obsessive-compulsive disorder. International Journal of Psychiatry in Clinical Practice, 16(4), 277–283. https://doi.org/10.3109/13651501.2011.653375. Walitza, S., Bove, D. S., Romanos, M., Renner, T., Held, L., Simons, M., … Grunblatt, E. (2012). Pilot study on HTR2A promoter polymorphism, -1438G/ A (rs6311) and a nearby copy number variation showed association with onset and severity in early onset obsessive-compulsive disorder. Journal of Neural Transmission (Vienna), 119(4), 507–515. https://doi.org/10.1007/s00702-011-0699-1. Walitza, S., Marinova, Z., Grunblatt, E., Lazic, S. E., Remschmidt, H., Vloet, T. D., & Wendland, J. R. (2014). Trio study and meta-analysis support the association of genetic variation at the serotonin transporter with early-onset obsessive-compulsive disorder. Neuroscience Letters, 580, 100–103. https://doi.org/10.1016/j.neulet.2014.07.038. Walitza, S., Wewetzer, C., Gerlach, M., Klampfl, K., Geller, F., Barth, N., … Hinney, A. (2004). Transmission disequilibrium studies in children and adolescents with obsessive-compulsive disorders pertaining to polymorphisms of genes of the serotonergic pathway. Journal of Neural Transmission (Vienna), 111(7), 817–825. https://doi.org/10.1007/s00702-004-0134-y. Willsey, A. J., Fernandez, T. V., Yu, D., King, R. A., Dietrich, A., Xing, J., … Heiman, G. A. (2017). De novo coding variants are strongly associated with Tourette disorder. Neuron, 94(3), 486–499. e489. https://doi.org/10.1016/j.neuron.2017.04.024.

252

Personalized Psychiatry

Wolf, C., Mohr, H., Schneider-Axmann, T., Reif, A., Wobrock, T., Scherk, H., … Gruber, O. (2014). CACNA1C genotype explains interindividual differences in amygdala volume among patients with schizophrenia. European Archives of Psychiatry and Clinical Neuroscience, 264(2), 93–102. https://doi.org/10.1007/s00406-013-0427-y. Wu, K., Hanna, G. L., Easter, P., Kennedy, J. L., Rosenberg, D. R., & Arnold, P. D. (2013). Glutamate system genes and brain volume alterations in pediatric obsessive-compulsive disorder: A preliminary study. Psychiatry Research, 211(3), 214–220. https://doi.org/10.1016/j. pscychresns.2012.07.003. Yoon, D. Y., Rippel, C. A., Kobets, A. J., Morris, C. M., Lee, J. E., Williams, P. N., … Singer, H. S. (2007). Dopaminergic polymorphisms in Tourette syndrome: Association with the DAT gene (SLC6A3). American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 144B(5), 605–610. https://doi.org/10.1002/ajmg.b.30466. Yu, D., Mathews, C. A., Scharf, J. M., Neale, B. M., Davis, L. K., Gamazon, E. R., … Pauls, D. L. (2015). Cross-disorder genome-wide analyses suggest a complex genetic relationship between Tourette’s syndrome and OCD. The American Journal of Psychiatry, 172(1), 82–93. https://doi.org/10.1176/ appi.ajp.2014.13101306. Yuan, A., Su, L., Yu, S., Li, C., Yu, T., & Sun, J. (2015). Association between DRD2/ANKK1 TaqIA polymorphism and susceptibility with Tourette syndrome: A meta-analysis. PLoS One, 10(6). https://doi.org/10.1371/journal.pone.0131060. Yue, W., Cheng, W., Liu, Z., Tang, Y., Lu, T., Zhang, D., … Huang, Y. (2016). Genome-wide DNA methylation analysis in obsessive-compulsive disorder patients. Scientific Reports, 6, 31333. https://doi.org/10.1038/srep31333. Zai, G., Bezchlibnyk, Y. B., Richter, M. A., Arnold, P., Burroughs, E., Barr, C. L., & Kennedy, J. L. (2004). Myelin oligodendrocyte glycoprotein (MOG) gene is associated with obsessive-compulsive disorder. American Journal of Medical Genetics. Part B, Neuropsychiatric Genetics, 129B(1), 64–68. https://doi.org/10.1002/ajmg.b.30077. Zai, G., Brandl, E. J., Muller, D. J., Richter, M. A., & Kennedy, J. L. (2014). Pharmacogenetics of antidepressant treatment in obsessive-compulsive disorder: An update and implications for clinicians. Pharmacogenomics, 15(8), 1147–1157. https://doi.org/10.2217/pgs.14.83. Zai, G., Zai, C. C., Arnold, P. D., Freeman, N., Burroughs, E., Kennedy, J. L., & Richter, M. A. (2015). Meta-analysis and association of brain-derived neurotrophic factor (BDNF) gene with obsessive-compulsive disorder. Psychiatric Genetics, 25(2), 95–96. https://doi.org/10.1097/ YPG.0000000000000077. Zhang, K., Cao, L., Zhu, W., Wang, G., Wang, Q., Hu, H., & Zhao, M. (2015). Association between the efficacy of fluoxetine treatment in obsessivecompulsive disorder patients and SLC1A1 in a Han Chinese population. Psychiatry Research, 229(1–2), 631–632. https://doi.org/10.1016/j. psychres.2015.06.039. Zhang, L., Liu, X., Li, T., Yang, Y., Hu, X., & Collier, D. (2004). Molecular pharmacogenetic studies of drug responses to obsessive-compulsive disorder and six functional genes. Zhonghua Yi Xue Yi Chuan Xue Za Zhi, 21(5), 479–481. Zilhao, N. R., Olthof, M. C., Smit, D. J., Cath, D. C., Ligthart, L., Mathews, C. A., … Dolan, C. V. (2017). Heritability of tic disorders: A twin-family study. Psychological Medicine, 47(6), 1085–1096. https://doi.org/10.1017/S0033291716002981. Zilhao, N. R., Padmanabhuni, S. S., Pagliaroli, L., Barta, C., BIOS Consortium, Smit, D. J., … Boomsma, D. I. (2015). Epigenome-wide association study of Tic disorders. Twin Research and Human Genetics, 18(6), 699–709. https://doi.org/10.1017/thg.2015.72. Zilhao, N. R., Smit, D. J., Boomsma, D. I., & Cath, D. C. (2016). Cross-disorder genetic analysis of Tic disorders, obsessive-compulsive, and hoarding symptoms. Frontiers in Psychiatry, 7, 120. https://doi.org/10.3389/fpsyt.2016.00120.